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Teratology and Drug Use During Pregnancy

  • Author: Brittney D Bastow, MD; Chief Editor: Christine Isaacs, MD  more...
 
Updated: Mar 24, 2016
 

Overview

Approximately 3-5% of live births are complicated by a birth defect each year totaling around 120,000 babies[1] .  Drug use is an uncommon cause of birth defects, but certain medications can increase the likelihood of developing a birth defect.   Additionally, more women taking any kind of medication has more than doubled in the last 30 years[2] .  Current evidence suggests that between 65%-94 % of women take at least one prescription drug during pregnancy[3, 4] .  Nearly 70% of women are taking a medication in the first trimester during organogenesis[3] .  On average, women are taking 3 medications in pregnancy[4] with over 50% of women using four or more[3] .  This includes over the counter medications and herbal supplements.

The purpose of this article is to provide an up to date source of information about medication use in pregnancy, to review the US Food and Drug Administration (FDA) pregnancy and lactation categories, and to further describe the recent FDA changes in drug labeling from December 2014.

 

 

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Approach to Patients Needing Medication During Pregnancy

Because any medication can present risks in pregnancy, and because not all risks are known, the safest pregnancy-related pharmacy is as little pharmacy as possible. However, women with underlying medical or psychiatric issues frequently require medication throughout pregnancy. In such patients, care must to be taken to select the safest drug from the necessary class of medication. Misri and Kendrick noted that prescribing drugs for women during the antenatal and postnatal period is a balancing act and that no risk-free alternatives exist [5]

Each area of pharmacologic therapy intervention must be assessed separately and specifically for each patient. For example, gastroesophageal reflux disease (GERD) is common during pregnancy and presents difficulties in choosing optimal medications.[6] For most patients, lifestyle modifications are useful, but if these interventions are insufficient to control symptoms, and medication is often required. First-line medical therapy for pregnant woman with GERD entails antacids. If antacids fail, use of histamine-2 receptor antagonists and proton-pump inhibitors can be attempted; these drugs do not seem to be associated with clinically significant risks in pregnancy. In rare cases, promotility agents can be prescribed, though the risks and benefits must carefully be discussed with the patients before the drugs are started.

A physician caring for a pregnant patient who requires medication should take care in choosing dosages and types of drugs that maximize effectiveness while minimizing fetal risk. It is essential to understand the effect of medications and to know the point in fetal development when drugs are most toxic and which fetal organs are most susceptible. In addition, healthcare providers who treat pregnant women must be familiar with methods of gathering information about drugs, and they must be aware of online databases that are most useful for this purpose.

Several resources are available to expand one’s knowledge of teratology. Teratogen Information System (TERIS) and Reprotox are Internet databases that cover this subject. The Organization of Teratology Information Specialists is a network of risk-assessment counselors in the United States and Canada who specialize in researching and communicating the risks associated with drug exposures in pregnancy. All of these are useful resources to learn about drug use in pregnancy. They are frequently updated and should be referenced frequently, particularly when one is prescribing unfamiliar drugs in pregnancy.  Primary literature searches via MEDLINE can also provide information about human data, clinical trials, and meta-analyses regarding a particular drug.[3]   Finally, the drug label can provide information about toxicity.  Since 1979 the FDA has provided a labeling system in an attempt to guide providers in prescribing drugs to pregnant women.  This system will be discussed later in the article.

General guidelines for choosing dosages and types of drugs within a class are lacking. Each drug should be assessed, and its risks and benefits should be weighed. Various organizations, including the Organization of Teratology Information Specialists, have performed many studies in this area. Specific drugs should be investigated before they are used.

Risk-benefit assessment and counseling should involve the patient in the setting of her current state of health. The physician must consider the effects of drug exposure on the developing fetus or embryo and acknowledge specific susceptibilities at each point in fetal development, as balanced against the risks of worsening maternal illness.  The patient must consider her symptoms, quality of life, and weigh risks and benefits of treatment.  The most important consideration is the underlying disease and the consideration of the consequences of interrupting or stopping treatment.[3]

In a 2008 Canadian study, 19.4% of women were found to have used FDA category C, D and X medications at least once during pregnancy, the most common of these being albuterol, co-trimoxazole, ibuprofen, naproxen and oral contraceptives.[7] Analyzing the same data, Yang noted that woman who had such exposure were more commonly characterized by chronic diseases, younger age, increased parity, and receipt of social assistance.[8]

Combinations of medications rather than individual medicines are possibly associated with increased risk of birth defects.  Oberlander et al performed a study to determine a population-based incidence of congenital anomalies following prenatal exposure to serotonin reuptake inhibitor antidepressants used alone and in combination with benzodiazepines. In this study, population health data, maternal health, and prenatal prescription records were linked to neonatal records, representing all live births in British Columbia during a 39-month period (1998-2001). Even after controlling for maternal illness profiles, infants exposed to prenatal serotonin reuptake inhibitors in combination with benzodiazepines had an increased incidence of congenital heart disease versus controls who had not been exposed. Serotonin reuptake inhibitor monotherapy was not associated with an increased risk for major congenital anomalies, but was associated with an increased incidence of atrial septal defects, and researchers did not associate risk with first trimester medication dose/day.[9]

Grigoriadis et al concluded that antidepressants do not seem to be associated with increased risk of congenital malformations, but evidence showed a statistical significance for cardiovascular malformations.[10]

For excellent patient education resources, visit eMedicineHealth's Pregnancy Center and Cholesterol Center. In addition, see eMedicineHealth's patient education articles Pregnancy, High Cholesterol, Cholesterol FAQs, and Lovastatin (Mevacor, Altocor).

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Example Mechanisms of Teratogenesis

In 1977 James Wilson proposed six principles of teratology that were subsequently published in the Handbook of Teratology.  The six principles he identified are:

1.    Susceptibility to teratogenesis depends upon the genotype of the conceptus and how it interacts with environmental Factors. 

2.    Susceptibility to teratogenic agents varies with the developmental stage at the time of exposure

3.    Teratogenic agents act in specific ways on developing cells and tissue to initiate abnormal embryogenesis.

4.    The final manifestations of abnormal development are death, malformation, growth retardation, and functional disorder.

5.    The access of adverse environmental influences to developing tissues depends on the nature of the agent.

6.    Manifestations of deviant development increase in degree as dosage increases from the no-effect to the totally lethal effect.     [11]

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Drug Exposures in the Male Partner

Research is increasingly addressing the role of paternal exposure to medications before conception or during his partner’s pregnancy. Certain exposures may alter the size, shape, performance, and production of sperm. This observation suggests that drug exposure in the male may put the fetus at risk. Animal studies have shown that paternal teratogenic exposure may lead to pregnancy loss or failure of the embryo to develop. However, unlike teratogenic agents taken by pregnant woman, teratogenic agents affecting the father do not seem to directly interfere with normal fetal development. Animal studies show that paternal teratogenic exposure may lead to pregnancy loss or embryonic failure.[12, 13]

At present, no evidence shows that paternal exposure directly increases the risk of birth defects.  A large cohort of over 340,000 pregnancies in Norway did not find paternal drug exposure to be a particularly important cause of birth defects or adverse pregnancy outcomes, especially after controlling for confounding factors with maternal exposure[14] .   Agents such as recreational drugs do affect sperm quality and, to a limited degree, indirectly expose the developing fetus to the substance. Rather than affecting the developing fetus, teratogen exposures like illicit drugs and alcohol seem to lower the likelihood of a woman's becoming pregnant rather than resulting in adverse pregnancy outcomes.[12, 13]

Paternal alcohol use may increase the risk of heart defects in newborns. In one study, paternal smoking was associated with heart defects. Chemotherapy or radiation therapy to treat cancer in a father may increase the risk chromosomal abnormalities of the fetus. Studies have demonstrated less-than-normal numbers of chromosomes and damage to the structure of chromosomes in the sperm of men with cancer. No data suggests an increased rate of birth defects in fetuses conceived with sperm from male chemotherapy patients.[15, 16]

Paternal exposure to prescription medications, such as cholesterol- and blood pressure–lowering drugs, has not been linked to a risk of birth defects. Additional research must clearly be conducted to assess the safety of drugs recently released onto the market. Regardless of the lack of evidence supporting a direct influence of paternal exposure on fetal risk, caution is warranted, and the father's physician should provide counseling and active involve the patient.

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FDA Rating System for the Teratogenic Effects of Drugs

The first regulations to drug labeling were implemented in 1962 after the exposure of over 10,000 children to thalidomide[2, 17] .  The 5-letter classification system (A, B, C, D, X) was then introduced in 1979 by the FDA.  These categories were developed based on the amount and quality of research done on the medication, not the safety of the medication in pregnancy or lactation.  It has been demonstrated that these categories, while relied upon to guide treatment of pregnant and lactating women, have been misinterpreted and are being misused[2, 4] .  Additionally, approximately 66% of all drugs are listed as category C indicating there is limited information about the safety of these medications[4] .  Thus, the 5-letter system is being phased out over the next 3 years in favor of a more comprehensive system with a narrative summary of the risks posed by drugs.

The FDA, the government agency that oversees the safety of drugs, provides the most widely used system to grade the teratogenic effects of medications. Each drug summary will have three sections: pregnancy, lactation, and females and males of reproductive potential.  “Pregnancy” merges previous categories of “pregnancy” and “labor and delivery.”  “Lactation” replaces “breastfeeding mothers” and all medications will be required to have this section[2] .  “Females and males of reproductive potential” is a new category to include information about pregnancy testing, contraception requirements, and effects on fertility before, during, and after drug therapy.

An additional requirement with the new FDA classification system, is the inclusion of information about pregnancy exposure registries under the “pregnancy” category.  Contact information needed to enroll in the registry or obtain information about the registry will be included as well.

In June 2015, the FDA shifted from the A, B, C, D, X categorization system to a new system for all drugs which enter the market after this time, and requires removal of the old categorization from all drug product labeling for drugs on the market over the next three to four years.  The pregnancy subsection is now presented under the following subheadings:

  1. Pregnancy Exposure Registry
  2. Risk Summary
  3. Clinical Considerations
  4. Data
    1. Pregnancy Exposure Registry
      1. If there is a scientifically acceptable pregnancy exposure registry for the drug, the contact information (toll free number or website) needed to enroll in or obtain information about the registry must be provided.  The availability of a pregnancy exposure registry should be noted in the patient counseling information. 
    2. Risk Summary
      1. This is always required. Provides “risk statements” that describe for the drug, the risk of adverse developmental outcomes bases on all relevant human data, animal data, and the drugs pharmacology.  Adverse developmental outcomes include the four groups of developmental toxicities:
      2. - "Structural abnormalities" describes dysmorphology, which includes malformations, variations, deformations, and disruptions.
      3. - "Embryo-fetal and/or infant mortality" describes development mortality, which includes miscarriage, stillbirth, and infant death (including neonatal death).
      4. - "Functional impairment" describes functional toxicity, which includes such outcomes as deafness, endocrinopathy, neurodevelopmental effects, and impairment of reproduction.
      5. - "Alterations to growth" describes outcomes such as growth restriction, excessive growth, and delayed or early maturations.
      6. When multiple data sources are available, risk statements must be presented in the following order: human, animal, and pharmacologic.  The risk summary should be presented as an integral summary and not as an individual listing of information.  If there is more than one risk based on human data, the information should be placed in order of clinical importance.
    3. Clinical Considerations See the list below:
      1. Relevant information is presented under the following five headings, to the extent information is available:
      2. - Disease-associated maternal and/or embryo/fetal risk
      3. - Dose adjustments during pregnancy and the postpartum period
      4. - Maternal adverse reactions
      5. - Fetal/Neonatal adverse reactions
      6. - Labor or Delivery
    4. Data
      1. --Under the subheading Data, labeling must describe the data that provide the scientific basis for the information presented in the Risk Summary and Clinical Considerations. This subheading is required, as are the headings Human Data and Animal Data, to the extent information is available. Human data and animal data must be presented separately, and human data must be presented first. ]]>--Under the subheading Data, labeling must describe the data that provide the scientific basis for the information presented in the Risk Summary and Clinical Considerations. This subheading is required, as are the headings Human Data and Animal Data, to the extent information is available. Human data and animal data must be presented separately, and human data must be presented first. ]]>
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Drugs That Reportedly Cause Birth Defects

Data for specific agents in the sections that follow were assembled to assist the provider in weighing the risks and benefits before beginning or continuing their use pregnancy. Information was compiled by selecting commonly used drugs, with an emphasis on recently approved agents.

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Discussion of Specific Agents: Antibiotics, Antiviral, Antiretroviral

Aminoglycosides (Amikacin, Gentamycin, Kanamycin, Tobramycin, Neomycin, and Streptomycin)

  • Old categorization: Pregnancy category - D
  • Risk summary: Trimester of risk - not consistent. Associated defects and complications: Some neonates have had hearing defects, whereas others have had vestibular problems. Some offspring had inner ear damage, whereas others did not.
  • Data: Since 1950, approximately 50 cases of fetal ototoxicity have been described after maternal exposure to either streptomycin or its congener dihydrostreptomycin. Ten cases of fetal ototoxicity have been described with kanamycin, a related drug. These cases occurred when high doses were used to treat tuberculosis. Gentamicin may be ototoxic to adults and to developing fetuses. Evidence indicates that fetal kidney selectively takes up gentamicin, which can result in cellular damage (probably reversible) to immature nephrons. In addition, inner ear damage or hearing defects have been induced in utero in rats and guinea pigs exposed to streptomycin and/or kanamycin.

Antiretrovirals (Abacavir, Didanosine, Emtricitabine, Lamivudine, Stavudine, Tenofovir, Zalcitabine, Zidovudine, Delavirdine, Efavirenz, Etravirine, Nevirapine, Rilpivirine, Atazanavir, Darunavir, Fosamprenavir, Indinavir, Lopinavir/ritonavir, Nelfinavir, Ritonavir, Saquinavir, Tipranavir, Raltegravir, Dolutegravir, Elvitegravir, Maraviroc, Enfuvirtide)

  • Old categorization: Pregnancy category B and C
  • Risk summary: Didanosine had increased risk of birth defects in first trimester as well as later in pregnancy. No specific pattern of defects was noted and clinical relevance is uncertain. Potential fetal safety concern: cynomolgus monkeys receiving efavirenz (EFV) during the first trimester at a dose resulting in plasma levels comparable to systemic human therapeutic exposure had 3 of 20 infants with significant CNS or other malformations.In humans, there is no increase in overall birth defects with first-trimester EFV exposure. However, in humans with first- trimester exposure, there have been 6 retrospective case reports and 1 prospective case report of CNS defects and 1 prospective case report of anophthalmia with facial clefts. The relative risk with first-trimester exposure is unclear. The remainder of the antiretrovirals appear to have minimal risk to the fetus with no higher incidence of birth defects.
  • Data: Studies in monkeys for tenofovir (at doses approximately 2-fold higher than that for human therapeutic use) show decreased fetal growth and reduction in fetal bone porosity within 2 months of starting maternal therapy. Human studies demonstrate no effect on intrauterine growth, but data are conflicting about potential outcomes later in infancy.

Cidofovir (Vistide)

  • Old categorization: Pregnancy category - C
  • Risk summary: Trimester of risk – Unknown. Associated defects and complications - Possible external, soft tissue, and skeletal anomalies (ie, meningocele, short snout, short maxillary bones) of the fetus
  • Clinical considerations: Cidofovir should be used during pregnancy only if the potential benefits justify the potential risks to the fetus.  Potential risk for carcinogenicity in the mother at higher doses.
  • Data: No adequate and well-controlled studies of cidofovir (Vistide; Gilead Sciences, Inc, Foster City, CA) have been performed in pregnant women. This drug was embryotoxic (reduced fetal body weights) in rats at 1.5 mg/kg/d and in rabbits at 1 mg/kg/d, dosages which were also maternally toxic with daily intravenous dosing during the period of organogenesis. The no-observable-effect levels for embryotoxicity in rats (0.5 mg/kg/d) and in rabbits (0.25 mg/kg/d) were respectively about 0.04 and 0.05 times the clinical dosage (5 mg/kg every other wk) based on the AUC. An increased prevalence of fetal external, soft tissue, and skeletal anomalies (ie, meningocele, short snout, short maxillary bones) occurred in rabbits at the high dosage of 1 mg/kg/d, which was also maternally toxic.

Fluconazole (Diflucan)

  • Old categorization: Pregnancy category - C (single dose); D (multiple doses)
  • Risk summary: Trimester of risk – First. Associated defects and complications - Craniofacial, skeletal, and cardiac effects
  • Data:  Available human data do not suggest an increased risk of congenital anomalies following a single maternal dose of 150 mg (Diflucan, Pfizer) for vaginal candidiasis. A few published case reports describe a rare pattern of distinct congenital anomalies in infants expose d in utero to high-dose maternal fluconazole (400-800 mg/d) during most or all of the first trimester; reported anomalies are similar to those seen in animal studies and consist of brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease.  Animal Studies: In several studies in which pregnant rats received fluconazole orally during organogenesis, maternal weight gain was impaired and placental weights were increased at 25 mg/kg. There were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 to 320 mg/kg (approximately 2 to 8 times the 400 mg clinical dose based on BSA), embryolethality in rats was increased and fetal abnormalities included wavy ribs, cleft palate, and abnormal cranio-facial ossification. These effects are consistent with the inhibition of estrogen synthesis in rats and may be a result of known effects of lowered estrogen on pregnancy, organogenesis, and parturition

Tetracyclines (Doxycycline, Tetracycline, Minocycline, Demeclocycline, Tigecycline)

  • Old Categorization: Pregnancy category - D
  • Risk Summary: Trimesters of risk - Second and third (20th gestational week or later).  Associated defects and complications - Dental staining
  • Clinical Consideration: Use during the last half of pregnancy may cause permanent discoloration of the teeth to a yellow- gray/brown color.  This class of drug should not be used during pregnancy.
  • Data: As little as 1 g/d of tetracycline for 3 days during the third trimester can produce yellow staining of deciduous teeth. After their eruption, yellow-stained teeth gradually darken to brown. Calcification of deciduous teeth begins at the end of the fourth month of gestation and ends at approximately 11-14 months of age. Administration of tetracycline to pregnant women in the second and third trimesters results in staining of dentine, with calcification of the enamel at the time of administration. Because the permanent teeth begin calcifying after birth, they are not affected by prenatal exposure. Although several case reports have described malformations (including enamel hypoplasia) after tetracycline use in pregnancy, findings from relatively large studies have mostly been negative. Despite this finding, tetracycline has been referred to as a teratogen in numerous publications.

Tinidazole (Tindamax)

  • Old Categorization: Pregnancy category - C
  • Risk Summary: Trimesters of risk - First, second, and third.  Associated defects and complications - Variable
  • Clinical Consideration: Tinidazole crosses the placental barrier and enters fetal circulation, it should not be administered to pregnant patients in the first trimester.  Tinidazole can be detected in breast milk for up to 72 hours following administration. Interruption of breast-feeding is recommended during tinidazole therapy and for 3 days following the last dose.
  • Data: Use of tinidazole (Tindamax; Mission Pharmacal Company, San Antonio, TX) has not been studied in pregnant patients. Studies of pregnant mice indicated no embryonic-fetal toxicity or malformations at the highest dose level of 2500 mg/kg (approximately 6.3-fold the highest human therapeutic dose based on body surface area conversions).In a study of pregnant rats, a slightly elevated frequency of fetal mortality was observed at a maternal dose of 500 mg/kg (2.5 times the highest human therapeutic dose based on body surface area conversions).No biologically relevant neonatal developmental effects were observed in rat neonates after maternal doses as high as 600 mg/kg (3 times the highest human therapeutic dose based on body surface area conversions).

          

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Discussion of Specific Agents: Cardiovascular Medications

Angiotensin-converting enzyme (ACE) inhibitors (Benzapril, captopril, enalopril, fosinopril, lisinpril, moexipril, perindopril, quinapril, ramipril, and trandolapril)

  • Old categorization: Pregnancy category - C or D
  • Risk Summary: Trimesters of risk - First trimester (category C); second and third trimesters (category D).  Associated defects and complications: Reported complications in pregnancy included oligohydramnios, intrauterine growth restriction (IUGR), premature labor, and fetal and neonatal renal failure. Reported birth defects included bony malformations, limb contractures, persistent patent ductus arteriosus, pulmonary hypoplasia, respiratory distress syndrome, prolonged hypotension, neonatal death, fetal calvarial hypoplasia or aplasia, oligohydramnios, and renal anomalies.
  • Clinical Consideration: Recommendation to stop an ACE inhibitor as soon as possible if a patient is discovered to be pregnant.
  • Data: One study demonstrated successful pregnancy outcomes (ie, live, healthy infant without severe disability at 2 y after delivery) in 87.5% of patients taking ACE inhibitors at any time during pregnancy. Boix et al reported a case of exencephaly and unilateral renal agenesia in a fetus of a woman with diabetes who became pregnant while taking irbesartan. [18] In a retrospective cohort study, Li et al found that during the first trimester the risk of malformations with the use of ACE inhibitors is similar to the use of other antihypertensives; the authors hypothesized that the apparent increased risk of malformations is due more to the mother’s underlying hypertension rather than the medications. [19]

Amlodipine/atorvastatin (Caduet)

  • Old categorization: Pregnancy category - X
  • Risk summary: Trimesters of risk - First, second, and third. Associated defects and complications - Variable; spina bifida
  • Clinical considerations: Amlodipine/atorvastatin (Caduet; Pfizer Inc, New York, NY) should be administered to women of childbearing only if they are highly unlikely to become pregnant and if they have been informed of the potential hazards associated with ingestion during pregnancy. If the patient becomes pregnant while taking this drug, therapy should be discontinued, and the patient should be informed of the potential hazards to the fetus.
  • Data: There are no adequate and well-controlled studies of atorvastatin use during pregnancy. There have been rare reports of congenital anomalies following intrauterine exposure to statins. In a review of about 100 prospectively followed pregnancies in women exposed to other statins, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. However, this study was only able to exclude a three-to-four-fold increased risk of congenital anomalies over background incidence. In 89% of these cases, drug treatment started before pregnancy and stopped during the first trimester when pregnancy was identified. Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. Atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure based on surface area (mg/m2).  Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). Because 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they may cause fetal harm when administered to pregnant women.

Angiotensin II receptor antagonists, angiotensin II receptor blockers [ARBs]  (cadesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan)

  • Old categorization: Pregnancy category - D
  • Risk summary: Trimesters of risk - First, second, and third. Associated defects and complications - Hypotension, renal dysplasia, anuria or oliguria, oligohydramnios, IUGR, pulmonary hypoplasia, patent ductus arteriosus, incomplete ossification of the skull, and intrauterine or neonatal death
  • Clinical considerations: Because of the severity of these complications, use of ARBs should be avoided throughout pregnancy and in women who are breastfeeding.
  • Data: Data from recent animal studies confirmed that intrauterine or neonatal exposure to ACE inhibitors or the ARB losartan can cause death and serious irreversible organ damage. Data from animal studies suggested that the toxic actions were most common after exposure during the last trimester.

Aspirin

  • Old classification: Pregnancy category  D
  • Risk Summary: Trimesters of risk – First, second, and third. Low dose may be acceptable as lower risk.  Associated defects and complications - Unclear; may be associated with an increased risk of gastroschisis.  Risks seem to be associated with dosing. High-dose aspirin (2 g per day) has been associated with stillbirths, cerebral hemorrhage, oculoauriculovertebral dysplasia, neonatal salicylate toxicity, constricted ductus arteriosus, cyclopia, and neonatal acidosis. Some cases of congenital heart defects have been reported.
  • Data: In a meta-analysis, no evidence of an overall increase in the risk of congenital malformations was reported associated with aspirin. Aspirin exposure during the first trimester may be associated with an increased risk of gastroschisis. A study of the use of low-dose aspirin (60 mg per day) to prevent and treat preeclampsia in 9364 pregnant women (the Collaborative Low-dose Aspirin Study in Pregnancy--CLASP) did "not support routine prophylactic or therapeutic administration of antiplatelet therapy in pregnancy to all women at increased risk of preeclampsia or IUGR." In that study, no excess of intraventricular hemorrhage, neonatal bleeds, or mortality attributable to bleeding were observed. The investigators did identify a possible role for low-dose aspirin in the treatment of early-onset preeclampsia severe enough to need very preterm delivery. Another study of low-dose aspirin (follow-up from the Italian Study of Aspirin in Pregnancy) has suggested that "low dose aspirin in pregnancy is safe with respect to the risks of malformation and of major impairment in development at 18 months of age." High-dose aspirin (2 g per day) has been associated with stillbirths, cerebral hemorrhage, oculoauriculovertebral dysplasia, neonatal salicylate toxicity, constricted ductus arteriosus, cyclopia, and neonatal acidosis. Some cases of congenital heart defects have been reported. However, a case control study of aspirin use in the first trimester concluded that aspirin "does not increase the risk of congenital heart defects in relation to that of other structural malformations."

Atenolol (Tenormin)

  • Old categorization: Pregnancy category - D
  • Risk summary: Trimesters of risk - First, second, and third. Associated defects and complications - IUGR
  • Data: There are no studies for use in the first trimester. Animal and human studies have shown growth retardation in humans and animals, as well as growth and structural abnormalities in animals. Reduced fetal size is a function of the length of exposure to the medication. The earlier the treatment starts, the greater the incidence of defects.  Beta blocker use has been associated with decreased placental perfusion, and may lead to intra-uterine deaths, immature and premature deliveries.

Statins (HMG-CoA reductase inhibitors) (Atorvastatin, Simvastatin, Rosuvastatin, Pravastatin, Lovastatin, Fluvastatin, Pitavastatin, Cerivastatin, Mevastatin)

  • Old Categorization: Pregnancy category - X
  • Risk Summary: Trimesters of risk - First, second, and third. Associated defects and complications - Possible spina bifida
  • Clinical Consideration: Lipid lowering drugs offer no benefit during pregnancy because cholesterol and cholesterol derivatives are needed for normal fetal growth.  Women of childbearing potential should be advised to use effective contraception during treatment.
  • Data: The causal nature of these defects remains to be fully defined. These drugs did no cause birth defects in rabbit testing.
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Discussion of Specific Agents: Neurologic Medications

Anticonvulsants, first-generation (Phenytoin, carbamazepine, valproate, ethosuximide, primidone)

  • Old categorization: Pregnancy category - D in general
  • Risk summery: Trimesters of risk - First, second, and third.  Associated defects and complications - Facial dysmorphia, gingival hyperplasia, neurological hyperexcitability and multiple malformations including (for valproic acid) predominantly temporal atrophy in the left brain hemisphere
  • Data: In a retrospective cohort study published in the New England Journal of Medicine, investigators examined newborns who were exposed to anticonvulsants in utero, born to mothers with epilepsy who did not take anticonvulsants, or born to mothers without epilepsy or a history of seizures. Birth defects occurred most frequently in infants exposed to anticonvulsants. About 20% of neonates exposed to 1 drug had birth defects; 28% exposed to 2 or more drugs had birth defects. Major birth defects were found in 4% of 223 babies whose mothers had taken 1 drug during pregnancy and in 8.6% of 93 whose mothers had taken 2 or more drugs. 23 Others researchers state that the risk doubles when 2 drugs are taken and that the risk is 10-fold higher than the risk in the control population when women take 4 anticonvulsants. Babies of mothers with epilepsy who were not treated with anticonvulsants were at no greater risk for having birth defects than were babies of mothers without epilepsy.

Carbamazepine (Tegretol, Carbatrol)

  • Old categorization: Pregnancy category - D
  • Risk summary: Trimesters of risk - First, second, and third.  Associated defects and complications - Unique facial appearance, microcephaly, and limb defects, including complete or partial absence of a limb, overgrowth, or underdevelopment of the fingers, toes, and nails, fused limbs; spina bifida, growth retardation, developmental delay 24
  • Clinical considerations: Women should be warned of these dangerous and potentially fatal side effects before becoming pregnant.
  • Data: One study revealed a 2-fold increase in the rate of major congenital anomalies (12 of 160 carbamazepine subjects vs 18 of 560 unexposed control subjects, relative risk of 2.24, 95% confidence interval: 1.1-4.56%). Another finding was a birthweight reduction of approximately 250 g. Other reports indicated an increased risk for spina bifida of up to 1 (1%) per 100 compared with the population risk of 1-2 cases per 1000 births.  According to a study in the New England Journal of Medicine in 1989, fetal exposure to carbamazepine could interrupt fetal development and congenital malformation. The study observed 35 children who were prenatally exposed to the drug and found that 11 percent were born with craniofacial defects, 26 percent developed hypoplasia and 20 percent experienced developmental delay.

Ergotamine (Ergomar, Ergostat, Mirgranal)

  • Old categorization: Pregnancy category - X
  • Risk summary: Trimesters of risk - First, second, and third. Associated defects and complications - Low birth weight and preterm birth
  • Clinical considerations: Dihydroergotamine possesses oxytocic properties and, therefore, should not be administered during pregnancy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
  • Data: Studies have shown a possible association between low birthweight and/or preterm birth. Ergotamine treatment may be connected with ergotamine-induced vasoconstriction in the placenta of pregnant women. The effect of ergotamine was most obvious in male newborn infants, particularly after treatment in the third trimester.  There are no adequate studies of dihydroergotamine in human pregnancy, but developmental toxicity has been demonstrated in experimental animals. In embryo-fetal development studies of dihydroergotamine mesylate nasal spray, intranasal administration to pregnant rats throughout the period of organogenesis resulted in decreased fetal body weights and/or skeletal ossification at doses of 0.16 mg/day (associated with maternal plasma dihydroergotamine exposures [AUC] approximately 0.4-1.2 times the exposures in humans receiving the MRDD of 4 mg) or greater. A no effect level for embryo-fetal toxicity was not established in rats. Delayed skeletal ossification was also noted in rabbit fetuses following intranasal administration of 3.6 mg/day (maternal exposures approximately 7 times human exposures at the MRDD) during organogenesis. A no effect level was seen at 1.2 mg/day (maternal exposures approximately 2.5 times human exposures at the MRDD). When dihydroergotamine mesylate nasal spray was administered intranasally to female rats during pregnancy and lactation, decreased body weights and impaired reproductive function (decreased mating indices) were observed in the offspring at doses of 0.16 mg/day or greater. A no effect level was not established. Effects on development occurred at doses below those that produced evidence of significant maternal toxicity in these studies. Dihydroergotamine-induced intrauterine growth retardation has been attributed to reduced uteroplacental blood flow resulting from prolonged vasoconstriction of the uterine vessels and/or increased myometrial tone.

Natalizumab (Tysabri)

  • Old Categorization: Pregnancy category – C
  • Pregnancy risk exposure: 1-800-456-2255 Natalizumab Pregnancy Exposure Registry
  • Risk Summary: Trimester of risk – Unknown. Associated defects and complications - Unknown
  • Clinical Considerations: There are no adequate and well-controlled studies in pregnant women.  Natalizumab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
  • Data: In reproductive studies of monkeys and guinea pigs, no evidence of teratogenic effects was observed at dosages up to 30 mg/kg (7 times the human clinical dose based on body-weight comparison). In a study in which female guinea pigs were exposed to natalizumab during the second half of pregnancy, a small reduction in pup survival was noted at postnatal day 14 compared with controls (3 pups per litter for the group treated with 30 mg/kg natalizumab and 4.3 pups per litter for the control group).In 1 of 5 studies in which monkeys or guinea pigs were exposed during pregnancy, the abortion rate in monkeys treated with 30 mg/kg was 33% versus 17% in controls. No effects on abortion rates were noted in any other study. Natalizumab underwent transplacental transfer and yielded in utero exposure in developing guinea pigs and cynomolgus monkeys. When pregnant dams were exposed to natalizumab at approximately 7 times the clinical dose, serum levels in fetal animals at delivery were approximately 35% of maternal serum levels. A study of pregnant cynomolgus monkeys treated at 2.3-fold the clinical dose demonstrated natalizumab-related changes in the fetuses. The changes included mild anemia, reduced platelet counts, increased splenic weights, and reduced hepatic and thymic weights in association with increased splenic extramedullary hematopoiesis, thymic atrophy, and decreased hepatic hematopoiesis. Platelet counts were also reduced in offspring born to mothers treated with natalizumab at 7 times the clinical dose. This effect was reversed upon clearance of natalizumab. The offspring had no evidence of anemia. Because results of animal reproduction studies are not always predictive of human responses, this drug should be used during pregnancy only if it is clearly needed. If a woman becomes pregnant while taking natalizumab, discontinuation should be considered. Whether natalizumab is excreted in human milk is unknown. Because many drugs and immunoglobulins are excreted in human milk and because the potential for serious adverse reactions is unknown, a decision should be made about whether nursing or natalizumab should be discontinued; this should depend on the importance of therapy to the mother.

Phenobarbital or methylphenobarbital

  • Old Categorization: Pregnancy category - D
  • Risk Summary: Trimester of risk - Late in pregnancy. Associated defects and complications - Phenobarbital or methylphenobarbital slightly increases the risk of cleft palate or lip and congenital heart disease. These drugs can cause fetal addiction and newborn withdrawal symptoms or newborn hemorrhage
  • Clinical Consideration: There are no adequate and well-controlled studies in pregnant women.  This drug should be used during pregnancy only if clearly needed.
  • Data: Long-term use of phenobarbital late in pregnancy has been associated with transient neonatal sedation or withdrawal symptoms in infants. Features observed in these infants include hyperactivity, irritability, and tremors. Perinatal or neonatal hemorrhage has occasionally been observed in infants of women who took phenobarbital late in pregnancy. This phenomenon has been attributed to drug-induced suppression of synthesis of vitamin K–dependent clotting factors.

Phenytoin (Dilantin)

  • Old Categorization: Pregnancy category – D
  • Risk Summary: Trimester of risk – Unknown. Associated defects and complications - Varied Hand and foot defects include fingerlike thumbs, aplasia or hypoplasia of the distal phalanges, supernumerary phalangeal epiphyses, and clubfoot. Dermatoglyphic abnormalities consist of abnormal palmar creases and nail hypoplasia or aplasia. General defects include growth retardation, atypical facial appearance, hirsutism, and low hairlines. Facial problems include microcephaly, brachycephaly, midfacial hypoplasia, wide fontanels, metopic ridging, mild micrognathia, low-set deformed ears, blepharoptosis, mild hypertelorism, strabismus, short nose with a broad depressed bridge and epicanthal folds, cupid's bow of the upper lip, and occasionally cleft lip and palate. Reported torso abnormalities include short neck with mild webbing, widely spaced nipples, umbilical or inguinal hernia, and rib anomalies. Internal abnormalities include variable coarctation of the aorta, endocardial cushion defect, double-outlet right ventricle, ventricular septal defect, atrial septal defect, bicuspid pulmonic valve, and intestinal malrotation. Ambiguous genitalia are rarely associated with this syndrome. A patient with the dysmorphic characteristics of fetal hydantoin syndrome presented with unusual hyperpigmentation of several fingernails. Another neonate presented with gum hypertrophy, digitalization of the thumbs, hypoplasia of the distal phalanges and nails, epicanthal folds, pseudohypertelorism, epidermoid cyst, and geographic tongue. Onychopathy can be a monosymptomatic or mild form of this syndrome. This syndrome may be associated with neonatal acne.
  • Clinical Consideration: An increase in seizure frequency may occur during pregnancy because of altered pharmacokinetics.  Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women. Infant breastfeeding is not recommended.
  • Data: Phenytoin affects folate and vitamin K metabolism, which may increase fetal bleeding. Some investigators have suggested that vitamin K be administered to mothers taking phenytoin in the third trimester to prevent hemorrhage. However, the available evidence does not justify this policy of giving vitamin K throughout the last third of pregnancy to all women being treated with anticonvulsants. When used in pregnancy, phenytoin can cause a syndrome of birth defects referred to with various names, such as Dilantin congenital defects, fetal hydantoin syndrome (FHS), Meadow syndrome, congenital hydantoin syndrome, Dilantin syndrome, fetal Dilantin syndrome, fetal phenytoin syndrome, and hydantoin syndrome. Various malformations have been reported to occur because of phenytoin intake during pregnancy.

Pregabalin (Lyrica)

  • Old Categorization: Pregnancy category – C
  • Pregnancy risk exposure: Pregnant patients exposed to pregabalin should be enrolled in the NAAED Pregnancy Registry (1-888-233-2334 or http://www.aedpregnancyregistry.org/ ).
  • Risk Summary: Trimesters of risk – Unknown, possible first.  Associated defects and complications – Growth restriction and 
  • Clinical Consideration: There are no adequate and well-controlled studies in pregnant women.
  • Data: When pregnant rats were given pregabalin orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification. Fetal body weights were decreased at the highest dose. When pregnant rabbits were given pregabalin orally throughout the period of organogenesis, decreased fetal body weight and increased incidences of skeletal malformations, visceral variations, and retarded ossification were observed at the highest dose.

Trimethadione (Tridione)

  • Old Categorization: Pregnancy category – D
  • Pregnancy risk exposure: Patients exposed during pregnancy need to enroll in the NAAED Pregnancy Registry (1-888-233-2334).
  • Risk Summary: Trimesters of risk - First, second, and third.  Associated defects and complications - Malformed ears, cleft palate, cardiac defects, urogenital malformations, and skeletal abnormalities; delayed mental and physical development also observe
  • Clinical Consideration: Trimethadione should only be prescribed to women of childbearing potential if it is essential in the management of seizures.  If a patient becomes pregnant while taking trimethadione, termination should be considered.
  • Data: The rate of fetal loss is reportedly as high as 87%.

Valproic acid (Depacon, Depakene, Depakote, Stavzor)

  • Old Categorization: Pregnancy category – D
  • Pregnancy risk exposure: http://www.aedpregnancyregistry.org, 1-888-233-233
  • Risk Summary: Trimesters of risk - First, second, and third.  Associated defects and complications - Lumbosacral spina bifida with meningomyelocele or meningocele, often accompanied by midfacial hypoplasia, deficient orbital ridge, prominent forehead, congenital heart disease, and decreased postnatal growth
  • Clinical Consideration: Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition.  Valproate should not be used to treat women with epilepsy who are pregnant or who plan to become pregnant unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable.   Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate.  Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population.  To prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life.
  • Data: Data from one study suggested that exposure to valproate during the first trimester of pregnancy may have changed the ultrastructure of the placenta by altering the migration of trophoblast cells. Another demonstrated that some of the effects may be due to alterations of folate metabolism.  Meador et al found that in utero exposure to valproate as compared with other antiepileptic agents is associated with a lower IQ in children. The study took place over 5 years in 25 epilepsy centers in the United States and the United Kingdom. The design was a prospective, observational, cohort study of pregnant women with epilepsy who took a single agent (carbamazepine, lamotrigine, phenytoin, valproate). The cohort study assessed the neurodevelopmental outcomes of children who were exposed in utero to several different antiepileptic drugs. A planned interim analysis conducted when the children were 3 years of age reported lower mean IQ scores in children with in utero valproic acid exposure compared with the other antiepileptic drugs. This association was dose-dependent. The investigators concluded that valproate should not be used as a first-line agent in women of childbearing potential. [20] Meador KJ, Baker GA, Browning N, et al. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med. This interim analysis was updated in 2013 with data from children completing 6 years of follow-up. The final results of the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study showed that children exposed to valproate products while their mothers were pregnant had decreased IQs at age 6 compared to children exposed to other antiepileptic drugs.33Meador KJ, Baker GA, Browning N, Cohen MJ, Bromley RL, Clayton-Smith J, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol. The prescribing information was changed to reflect this risk including a Black Box Warning stating not to use valproate derivatives in women of childbearing age unless the drug is essential to the management of seizures, or for manic episodes associated with bipolar disorder (FDA fetal risk category D). It should not be used for migraine headache prophylaxis during pregnancy (FDA fetal risk category X).
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Discussion of Specific Agents: Psychiatric Medications

Benzodiazepines (alprazolam, chlordiazepoxide, clobazam, clonazepam, diazepam, estazolam, flurazepam, halazepam, lorazepam, midazolam, quazepam, temezapam, trazolam)

  • Old categorization: Pregnancy category - D or X. 
  • Risk summary: Trimesters of risk: The first, second, and third trimesters are times or risk for flurazepam, temazepam, and triazolam (category X). Chlordiazepoxide seems to be safe during pregnancy. Avoidance of alprazolam during pregnancy seems prudent.  Associated defects and complications - Unclear; potential for isolated oral cleft
  • Clinical considerations: Certain benzodiazepines should be avoided in pregnancy, such as triazolam. Others should be used with caution, and only if the benefits outweigh the risks.
  • Data: The information currently available is insufficient to determine whether the potential benefits of benzodiazepines to the mother outweigh the risks to the fetus. Pooled data from cohort studies show no association between fetal exposure to benzodiazepines and a risk of major malformations or oral cleft. However, pooled data from case-control studies demonstrated that the risk for major malformations is significantly increased, particularly for isolated oral cleft. Until additional research data are reported, level 2 ultrasonography is useful for assessing the patient for a cleft lip.

Bupropion (Wellbutrin, Zyban)

  • Old Categorization: Pregnancy category - C
  • Risk Summary: Trimesters of risk – Unknown.  Associated defects and complications – Unknown
  • Clinical Consideration: Consider the risk of untreated depression when discontinuing or changing treatment in pregnancy and postpartum
  • Data: No clear evidence of teratogenic activity was found in reproductive developmental studies conducted in rats and rabbits; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at doses approximately equal to the maximum recommended human dose (MRHD) and greater and decreased fetal weights were seen at doses twice the MRHD and greater. Bupropion should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Data from the bupropion Pregnancy Registry and a retrospective cohort study using United Healthcare database did not show an increased risk for malformations overall.

Duloxetine (Cymbalta)

  • Old categorization:  Pregnancy category – C.
  • Pregnancy risk exposure: 1-866-814-6975, www.cymbaltapregnancyregistry.com
  • Risk summary: There are no adequate and well-controlled studies of CYMBALTA administration in pregnant women. In animal studies with duloxetine, fetal weights were decreased but there was no evidence of teratogenicity in pregnant rats and rabbits at oral doses administered during the period of organogenesis up to 4 and 7 times the maximum recommended human dose (MRHD) of 120 mg/day, respectively. When duloxetine was administered orally to pregnant rats throughout gestation and lactation, pup weights at birth and pup survival to 1 day postpartum were decreased at a dose 2 times the MRHD. At this dose, pup behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity were observed. Post-weaning growth was not adversely affected. Duloxetine should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
  • Clinical Considerations: Fetal/Neonatal Adverse Reaction — Neonates exposed during pregnancy to serotonin - norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs) have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding which can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of the SNRIs or SSRIs, or possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome.
  • Data: Animal Data — In animal reproduction studies, duloxetine has been shown to have adverse effects on embryo/fetal and postnatal development.When duloxetine was administered orally to pregnant rats and rabbits during the period of organogenesis, there was no evidence of teratogenicity at doses up to 45 mg/kg/day (4 times the maximum recommended human dose (MRHD) of 120 mg/day on a mg/m 2 basis, in rat; 7 times the MRHD in rabbit). However, fetal weights were decreased at this dose, with a no-effect dose of 10 mg/kg/day approximately equal to the MRHD in rats; 2 times the MRHD in rabbits).When duloxetine was administered orally to pregnant rats throughout gestation and lactation, the survival of pups to 1 day postpartum and pup body weights at birth and during the lactation period were decreased at a dose of30 mg/kg/day (2 times the MRHD); the no-effect dose was 10 mg/kg/day. Furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity, were observed in pups following maternal exposure to 30 mg/kg/day. Post-weaning growth and reproductive performance of the progeny were not affected adversely by maternal duloxetine treatment.

Fluoxetine (Prozac)

  • Old categorization: Pregnancy category - C
  • Risk summary: Trimesters of risk - First, second, and third.  Associated defects and complications - Variable; possible self-limited neonatal behavioral syndrome
  • Clinical considerations: Fetal/neonatal: Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 - 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiological studies suggest a positive statistical association between SSRI use (including fluoxetine) in pregnancy and PPHN. Other studies do not show a significant statistical association.
  • Data: Reports of more than 1000 pregnancies exposed to fluoxetine (Prozac; Eli Lilly and Company) during the first trimester have been recorded. No study revealed an increased risk for major structural birth defects (ie, those requiring surgery or reducing function). One study has shown an increased rate of 3 or more minor birth defects (i.e., those not medically or functionally significant) among children exposed to fluoxetine in the first trimester. When 3 or more minor birth defects are seen together, the likelihood of a major birth defect (including learning problems) increases, though this effect was not observed in the fluoxetine study. Follow-up studies have been started to investigate the possible long-term effects on infants exposed to fluoxetine during pregnancy. The available evidence indicates that in utero exposure to serotonin reuptake inhibitors during the last trimester through delivery may result in a self-limited neonatal behavioral syndrome that can be managed with supportive care. Conflicting evidence exists regarding use of SSRIs during pregnancy and increased risk of persistent pulmonary hypertension of the newborn. An initial Public Health Advisory in 2006 was based on a single retrospective study; since then, there have been conflicting findings from new studies, making it unclear whether use of SSRIs during pregnancy can cause PPHN. [21] The FDA has reviewed the results of an additional new study and has concluded that, given the conflicting results from different studies, it is premature to reach any conclusion about a possible link between SSRI use in pregnancy and PPHN. The FDA is advising health care professionals not to alter their current clinical practice of treating depression during pregnancy and to report any adverse events to the FDA MedWatch program [22] See the list below:
    • Animal Data — In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of fluoxetine at doses up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/m2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m2 basis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/m2 basis).

Lithium

  • Old categorization: Pregnancy category – D.
  • Risk summary: Trimester of risk – Unknown.   Associated defects and complications - Variable; possible cardiac effects, especially Ebstein’s anomaly.
  • Clinical consideration: If the patient becomes pregnant while taking lithium, she should be apprised of the potential risk to the fetus. If possible, lithium should be withdrawn for at least the first trimester unless it is determined that this would seriously endanger the mother.
  • Data: In 1973, an International Register of Lithium Babies was established to monitor the outcome of fetuses exposed in the first trimester of pregnancy. As of 1990, 225 cases were registered, with 25 instances of malformation. Of these, 18 involved the great vessels of the heart. Six were Ebstein anomalies, defects affecting the tricuspid valve. These numbers suggest a greatly increased risk compared with the normal frequency of Ebstein anomaly (1 in 20,000 births). However, this claim has been contested on the grounds of over reporting of abnormal cases and because 2 studies returned negative findings. The question remains whether lithium is a human teratogen. The best estimate comes from cohort studies, one of which suggested an increased rate (4-12%) of congenital malformations compared with the rate observed in the general population (2-4%). In 1992, a prospective study of pregnancy outcomes after exposure to lithium carbonate during the first trimester of pregnancy was reported. [23] In it, 138 patients were successfully followed up to the end of pregnancy. The rate of congenital malformations was the same between lithium-exposed subjects (2.8%) and maternal age-matched control subjects (2.4%). However, 1 Ebstein anomaly was reported in the lithium group. Birth weight was notably increased in the lithium group despite identical gestational ages. One cohort study showed positive relative risks of 3 for all types of congenital malformations and 7.7 for cardiac malformations. None of the subjects had an Ebstein anomaly. Findings from a second cohort study were negative. Four case-control studies performed to test the association between lithium and Ebstein anomaly have also been reported. No cases of Ebstein anomaly were observed in 208 lithium-exposed embryos, though 2 cases were found among 398 control subjects.

Ramelteon (Rozerem)

  • Old Categorization: Pregnancy category - C
  • Risk Summary: Trimesters of risk – Unknown.  Associated defects and complications – Unknown
  • Clinical Consideration: Ramelteon should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
  • Data: No adequate and well-controlled studies have been performed in pregnant women.  Oral administration of ramelteon (10, 40, 150 or 600 mg/kg/day) to pregnant rats during the period of organogenesis was associated with increased incidences of fetal structural abnormalities (malformations and variations) at doses greater than 40 mg/kg/day. The no-effect dose is approximately 50 times the RHD on a body surface area (mg/m2) basis. Treatment of pregnant rabbits during the period of organogenesis produced no evidence of embryo-fetal toxicity at oral doses of up to 300 mg/kg/day (or up to 720 times the RHD on a mg/m 2 basis

Paroxetine (Paxil)

  • Old categorization: Category D
  • Risk Summary: Trimester of risk: first.  Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of congenital malformations, particularly cardiovascular malformations.
  • Data: A study based on Swedish national registry data demonstrated that infants exposed to paroxetine during pregnancy (n = 815) had an increased risk of cardiovascular malformations (2% risk in paroxetine-exposed infants) compared to the entire registry population (1% risk), for an odds ratio (OR) of 1.8 (95% confidence interval 1.1 to 2.8). No increase in the risk of overall congenital malformations was seen in the paroxetine-exposed infants. The cardiac malformations in the paroxetine-exposed infants were primarily ventricular septal defects (VSDs) and atrial septal defects (ASDs). Septal defects range in severity from those that resolve spontaneously to those who require surgery. -- ]]>A separate retrospective cohort study from the United States (United Healthcare data) evaluated 5,956 infants of mothers dispensed antidepressants during the first trimester (n = 815 for paroxetine). This study showed a trend towards an increased risk for cardiovascular malformations for paroxetine (risk of 1.5%) compared to other antidepressants (risk of 1%), for an OR of 1.5 (95% confidence interval 0.8 to 2.9). Of the 12 paroxetine-exposed infants with cardiovascular malformations, 9 had VSDs. This study also suggested an increased risk of overall major congenital malformations including cardiovascular defects for paroxetine (4% risk) compared to other (2% risk) antidepressants (OR 1.8; 95% confidence interval 1.2 to 2.8).Two large case-control studies using separate databases, each with >9,000 birth defect cases and >4,000 controls, found that maternal use of paroxetine during the first trimester of pregnancy was associated with a 2- to 3-fold increased risk of right ventricular outflow tract obstructions. In one study the odds ratio was 2.5 (95% confidence interval, 1.0 to 6.0, 7 exposed infants) and in the other study the odds ratio was 3.3 (95% confidence interval, 1.3 to 8.8, 6 exposed infants).
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Discussion of Specific Agents: Respiratory Medications

Leukotriene receptor antagonists (montelukast, pranlukast, zafirlukast)

  • Old categorization: Pregnancy category - B
  • Risk summary: Trimester of risk – Unknown. Associated defects and complications – Congenital limb defects have been rarely reported in offspring of women being treated with montelukast (Singlulair, Merck) during pregnancy.
  • Clinical consideration: There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, they should be used during pregnancy only if clearly needed.
  • Data: In a study by Bakhireva et al, perinatal outcomes among 96 women who took montelukast or zafirlukast were compared with those of 122 women who exclusively took short-acting beta2-agonists and 346 women without asthma. 27 No specific pattern of major structural anomalies in their offspring or a large risk of other adverse perinatal outcomes was found. Animal data - Teratogenic Effect: No teratogenicity was observed in rats and rabbits at doses approximately 100 and 110 times, respectively, the maximum recommended daily oral dose in adults based on AUCs.

Tiotropium bromide (Spiriva)

  • Old Categorization: Pregnancy category - C
  • Risk Summary: Trimester of risk – Unknown.  Associated defects and complications - Unknown
  • Clinical Consideration: Tiotropium bromide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus
  • Data: No evidence of structural alterations was observed in rats and rabbits at dosages of inhalation tiotropium (Spiriva HandiHaler; Pfizer Inc and Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT) of up to 1.471 and 0.007 mg/kg/d, respectively. These dosages corresponded to approximately 660 and 6 times RHDD on a milligram-per–square meter basis, respectively. However, in rats, fetal resorption, litter loss, decreases in the number of live pups at birth and mean pup weights, and a delay in pup sexual maturation were observed at inhalation dosages of 0.078 mg/kg (approximately 35 times the RHDD on a milligram-per–square meter basis). In rabbits, an increase in postimplantation loss was observed at an inhalation dosage of 0.4 mg/kg/d (approximately 360 times the RHDD on a milligram-per–square meter basis). Such effects were not observed at inhalation dosages of 0.009 and up to 0.088 mg/kg/d in rats and rabbits, respectively. These doses corresponded to approximately 4 and 80 times the RHDD on a milligram-per–square meter basis, respectively. These dosage multiples may have been overestimated because of difficulties in measuring deposited doses in animal inhalation studies. No adequate and well-controlled studies have been performed in pregnant women.  The safety and effectiveness of tiotropium has not been studied during labor and delivery.
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Discussion of Specific Agents: Oncologic and antineoplastic medications

Antineoplastics (busulfan, chlorambucil, cyclophosphamide, mechlorethamine)

  • Old categorization: Pregnancy categories - D and X
  • Risk summery: Trimesters of risk - First, second, and third.  Associated defects and complications: Observed problems included IUGR, cleft palate, renal agenesis, digital malformations, cardiac anomalies, and cloudy corneas. First-trimester exposure to antimetabolites (aminopterin, 5-fluorouracil, methotrexate, methylaminopterin, and cytarabine) produced a risk for cleft lip and palate, low-set ears, cranial anomalies, and anencephaly.
  • Data: Case series show that 10-50% of fetuses exposed to antineoplastic alkylating agents are malformed. The malformation rate for first-trimester exposure is 11.6%. Only case reports are available for antineoplastic antimetabolites; however, a mean of 40% of neonates were malformed.

Lenalidomide (Revlimid)

  • Old categorization: Pregnancy category – X
  • Pregnancy risk exposure: 1-888-423-5436
  • Risk summary: Trimesters of risk - First, second, and third. Associated defects and complications - Possible reduction in fetal body weight and increase in post-implantation losses and fetal variations
  • Clinical considerations: Fetal – Lenalidomide (Revlimid, Celgene) is a thalidomide analog. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants.
  • Data: Animal data.  In an embryo-fetal developmental toxicity study in monkeys, teratogenicity, including thalidomide-like limb defects, occurred in offspring when pregnant monkeys received oral lenalidomide during organogenesis.  Exposure (AUC) in monkeys at the lowest dose was 0.17 times the human exposure at the maximum recommended human dose (MRHD) of 25 mg.  Similar studies in pregnant rabbits and rats at 20 times and 200 times the MRHD, respectively, produced lethality in rabbits and n adverse reproductive effects in rats.  -- ]]>In a pre- and post-natal development study in rats, animals received lenalidomide from organogenesis through lactation. The study revealed a few adverse effects on the offspring of female rats treated with lenalidomide at doses up to 500 mg/kg (approximately 200 times the human dose of 25 mg based on body surface area). The male offspring exhibited slightly delayed sexual maturation and the female offspring had slightly lower body weight gains during gestation when bred to male offspring. As with thalidomide, the rat model may not adequately address the full spectrum of potential human embryo-fetal developmental effects for lenalidomide.

Mycophenolate mofetil (Cellcept)

  • Old Categorization: Pregnancy category – D
  • Pregnancy risk exposure: http://www.ntpr.giftoflifeinstitute.org
  • Risk Summary: Trimester of risk - First
    • Associated defects and complications - External ear and facial defects; cleft lip and palate; heart, esophagus, kidney and distal limb defects.  Associated with increased of first trimester pregnancy loss.
  • Clinical Consideration: Women of childbearing potential should receive contraceptive counseling and use effective contraception starting 4 weeks prior to initiating therapy.  Women using mycophenolate mofetil at any time during pregnancy should be encouraged to enroll in the National Transplantation Pregnancy Registry.
  • Data: The pregnancy category of mycophenolate mofetil was recently changed from C (risk of fetal harm from the drug cannot be ruled out) to D (existing evidence of fetal risk). Previous studies showed supporting results; most studies involved the use of mycophenolate mofetil during the preconception period and the first trimester.

Pemetrexed (Alimta)

  • Old Categorization: Pregnancy category - C
  • Risk Summary: Trimester of risk – Unknown.  Associated defects and complications - Unknown
  • Clinical Consideration: Pemetrexed may cause harm when administered to pregnant women.  Lactating women should discontinue nursing if being treated with pemetrexed.  Patients should be advised to avoid becoming pregnant.
  • Data: No adequate and well-controlled studies of pemetrexed (Alimta; Eli Lilly and Company) have been performed in pregnant women. Fetotoxic and teratogenic in mice at i.p. doses of 0.2 mg/kg (0.6 mg/m2) or 5 mg/kg (15 mg/m2) when given on gestation days 6 through 15. Pemetrexed caused fetal malformations (incomplete ossification of talus and skull bone) at 0.2 mg/kg (about 1/833 the recommended i.v. human dose on a mg/m2 basis), and cleft palate at 5 mg/kg (about 1/33 the recommended i.v. human dose on a mg/m2 basis).  Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes.

Thalidomide (Thalomid)

  • Old Categorization: Pregnancy category – X
  • Pregnancy risk exposure: Report any suspected fetal exposure to the FDA via the MedWatch program at 1-800-FDA-1088 and also to the Celgene Corporation at 1-888-423-5436.
  • Risk Summary: Trimesters of risk - First, second, and third
    • Associated defects and complications - Malformed intestines, hearing defects, absent ears, and/or ocular and renal anomalies, phocomelia
  • Clinical Consideration: If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.  The drug should be immediately discontinued. Females of reproductive potential must commit either to abstain continuously from heterosexual intercourse or to use two methods of reliable birth control simultaneously.  Males exposed to thalidomide must always use a latex or synthetic condom during any sexual contact with females of reproductive potential and for up to 28 days after discontinuing.
  • Data: Many mechanisms of action have been proposed for thalidomide, yet the true mechanism remains unknown. One theory suggests that neural crest cells are affected. Another mentions an alteration in metanephros-limb interaction that stunts the limb’s outgrowth. Other possibilities include a reduction in the size of ganglia (which inhibits limb development because limb growth depends on neuronal growth) or an inhibition of cell-to-cell interactions and reduced quantities of cell adhesion molecules; these alterations make limb growth impossible.

--In an embryo-fetal developmental toxicity study in monkeys, teratogenicity, including thalidomide-like limb defects, occurred in offspring when pregnant monkeys received oral lenalidomide during organogenesis. Exposure (AUC) in monkeys at the lowest dose was 0.17 times the human exposure at the maximum recommended human dose (MRHD) of 25 mg. Similar studies in pregnant rabbits and rats at 20 times and 200 times the MRHD respectively, produced embryo lethality in rabbits and no adverse reproductive effects in rats. ]]>

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Discussion of Specific Agents: Musculoskeletal and Rheumatic medications

Colchicine

  • Old categorization: Pregnancy category - C
  • Risk category: Trimester of risk – Unknown.  Associated defects and complications - Generally unknown; potential chromosome aberrations.
  • Clinical considerations: There are no adequate and well-controlled studies in pregnant women. Colchicine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
  • Data: Colchicine has been shown to cause birth defects in animals. Only a few reports describe it as causing birth defects in humans. Occasional cases of trisomy or aneuploidy have been reported in patients being treated with colchicine for gout. A causal relationship is uncertain. Some early studies suggested an increase in Down's syndrome, but that association appears to be coincidental. In a study of 28 women with familial Mediterranean fever (FMF) who were taking colchicine, 25% had miscarriages and 36% had periods of infertility. These rates were high but similar to rates reported for women with FMF without colchicine. All 16 babies born to the FMF women on colchicine were healthy. Pregnant patients with FMF who are receiving colchicine, may need to be monitored to determine renal function during pregnancy. A summary of 3 studies showed 4 of 14 men taking colchicine developed reversible azoospermia. When tested in mice given 1.25 to 1.5 mg/kg and hamsters given 10 mg/kg, colchicine was shown to be teratogenic. The drug can lower sperm counts and cause sperm defects, affecting the ploidy of sperm and resulting in birth defects.

Ibandronate (Boniva)

  • Old categorization: Pregnancy category - C
  • Risk summary: Trimester of risk – Unknown. Associated defects and complications – Unknown.
  • Clinical considerations: There is a theoretical risk of fetal harm (skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (oral vs iv) on this risk has not been established.
  • Data: No adequate and well-controlled studies have been conducted in pregnant women with Boniva (Roche). Animal data: In female rats given ibandronate orally at doses greater than or equal to 3 times human exposure at the recommended daily oral dose of 2.5 mg or greater than or equal to 1 times human exposure at the recommended once-monthly oral dose of 150 mg beginning 14 days before mating and continuing through lactation, maternal deaths were observed at the time of delivery in all dose groups. Perinatal pup loss in dams given 45 times human exposure at the recommended daily dose and 13 times the recommended once-monthly dose was likely related to maternal dystocia. Calcium supplementation did not completely prevent dystocia and periparturient mortality in any of the treated groups at greater than or equal to 16 times the recommended daily dose and greater than or equal to 4.6 times the recommended once-monthly dose. A low incidence of postimplantation loss was observed in rats treated from 14 days before mating throughout lactation or during gestation, only at doses causing maternal dystocia and periparturient mortality. In pregnant rats dosed orally from gestation day 17 through lactation day 21 (following closure of the hard palate through weaning), maternal toxicity, including dystocia and mortality, fetal perinatal and postnatal mortality, were observed at doses equivalent to human exposure at the recommended daily and greater than or equal to 4 times the recommended once-monthly dose. Periparturient mortality has also been observed with other bisphosphonates and appears to be a class effect related to inhibition of skeletal calcium mobilization resulting in hypocalcemia and dystocia

Penicillamine (Depen, Cuprimine)

  • Old Categorization: Pregnancy category - D
  • Risk Summary: Trimester of risk - Unknown
    • Associated defects and complications - Variable; possible connective-tissue defects, cerebral palsy, hydrocephalus, skeletal defects, cleft palates, and fetal toxicity (resorptions)
  • Clinical Consideration: Except for the treatment of Wilson’s disease or certain patients with cystinuria, use of penicillamine during pregnancy is contraindicated.  For patients with Wilson’s disease, it is recommended that the daily dosage be limited to 750 mg.  If cesarean delivery is planned, the daily dose should be reduced to 250 mg, but not lower, for the last 6 weeks of pregnancy and post-operatively until wound healing is complete.  Mothers using penicillamine should not nurse their infants.  Women on therapy with penicillamine who are of childbearing potential should be advised to report promptly any possible pregnancy and followed closely for early recognition of pregnancy.
  • Data: No controlled studies have been conducted on the use of penicillamine in pregnant women. Although normal outcomes have been reported, characteristic congenital cutis laxa and associated birth defects have been reported in infants born of mothers who received therapy with penicillamine during pregnancy. Penicillamine has been shown to be teratogenic in rats when given in doses 6 times higher than the highest dose recommended for human use. Skeletal defects, cleft palates and fetal toxicity (resorptions) have been reported.
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Discussion of Specific Agents: Genitourinary medications

Misoprostol (Cytotec, Arthrotec)

  • Old Categorization: Pregnancy category - X
  • Risk Summary: Trimesters of risk - First, second, and third.  Associated defects and complications - Möbius syndrome.  Several reports in the literature associate the use of misoprostol during the first trimester of pregnancy with skull defects, cranial nerve palsies, facial malformations, and limb defects.
  • Clinical Consideration: Cytotec should not be taken by pregnant women to reduce the risk of ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs).  Misoprostol may endanger pregnancy (may cause abortion) when administered to pregnant women.  Caution should be exercised when administered to nursing women.
  • Data: In a case-control study, researchers compared the frequency of misoprostol use during the first trimester between mothers of 96 Brazilian infants with Möbius syndrome and mothers of 96 infants with neural tube defects. Among the former, 47 (49%) had taken misoprostol during pregnancy, compared with just 3 (3%) of the mothers from the other group. Other investigators have stated that misoprostol use causes a 30-fold increase in the prevalence of Möbius syndrome, though this effect is still rare.

Solifenacin succinate (Vesicare)

  • Old Categorization: Pregnancy category - C
  • Risk Summary: Trimester of risk – Unknown.  Associated defects and complications - Unknown
  • Clinical Consideration: Pregnant women should not take solifenacin succinate, and women should not become pregnant while taking solifenacin succinate without first consulting a physician.  Women who are breastfeeding should not take solifenacin succinate without first talking to their physician
  • Data: Whether solifenacin succinate (VESIcare; GlaxoSmithKline and Astellas Pharma US, Inc, Deerfield, IL) is harmful to an unborn baby is not known. After oral administration of solifenacin succinate to pregnant mice, drug-related material was shown to cross the placental barrier. No embryotoxicity or teratogenicity was observed in mice treated with 1.2 times (30 mg/kg/day) the expected exposure at the maximum recommended human dose [MRHD] of 10 mg.

Trospium chloride (Sanctura)

  • Old Categorization: Pregnancy category - C
  • Risk Summary: Trimester of risk – Unknown.  Associated defects and complications - Unknown
  • Clinical Consideration: Based on animal data, trospium chloride is predicted to have a low probability of increased risk of adverse developmental outcomes, above background risk.  Trospium chloride should be used during pregnancy only if the potential benefits justify the potential risks to the fetus. It should be used during lactation only if the potential benefit justifies the potential risk to the newborn.
  • Data: No adequate and well-controlled studies have been performed in pregnant women. Trospium chloride (Sanctura; Esprit Pharmaceuticals, East Brunswick, NJ, and Indevus Pharmaceuticals, Inc, Lexington, MA) has been shown to cause maternal toxicity and decrease fetal survival in rats given approximately 10 times the expected clinical exposure (AUC). No-effect levels for maternal and fetal toxicity were approximately equivalent to the expected clinical exposure in rats and were approximately 5-6 times the expected clinical exposure in rabbits. No malformations or developmental delays were observed. Trospium chloride 2 mg/kg given orally and 50 mcg/kg given intravenously were excreted to a limited extent (< 1%) into the milk of lactating rats. The activity observed in the milk was primarily from the parent compound. Whether this drug is excreted in human milk is not known. Because many drugs are excreted in human milk, caution should be exercised when trospium chloride is administered to a nursing woman.

 

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Discussion of Specific Agents: Gastrointestinal medications

Ondansetron (Zofran)

  • Old Categorization: Pregnancy category - B
  • Risk Summary: Trimesters of risk - Unknown
    • Associated defects and complications – Unknown. Possible cleft lip and/or palate, possible cardiac septum
  • Clinical Consideration: Ondansetron should not be used as a first line agent for nausea and vomiting of pregnancy.
  • Data: Reproduction studies have been performed in pregnant rats and rabbits at intravenous doses up to 4 mg/kg per day (approximately 1.4 and 2.9 times the recommended human intravenous dose of 0.15 mg/kg given three times a day, respectively, based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to ondansetron. A prospective comparative observational study from TIS (Teratogen Information Services) in 2004 found no increased risk for major malformations above baseline risks.

Sulfasalazine (Azulifidine, Sulfazine)

  • Old Categorization: Pregnancy category – B
  • Risk Summary: Trimesters of risk: unknown
    • Associated defects and complications- unknown
  • Clinical Consideration: Sulfasalazine should be used during pregnancy only if clearly needed.
  • Data: Researchers in Iran performed a meta-analysis to explore the risk of adverse pregnancy outcomes in women with IBD following exposure to 5-ASA drugs (mesalazine, sulfasalazine, balsalazide, and olsalazine). This meta-analysis suggests that women taking 5-ASA drugs had no more than a 1.16-fold increase in congenital malformations, a 2.38-fold increase in stillbirth, a 1.14-fold increase in spontaneous abortion, a 1.35-fold increase in preterm delivery, and a 0.93-fold increase in low birth weight. [24]

Rifaximin (Xifaxan)

  • Old Categorization: Pregnancy category - C
  • Risk Summary: Trimesters of risk – Unknown.  Associated defects and complications - Possible cleft palate, agnathia, jaw-shortening, hemorrhage, eyes partially open, small eyes, brachygnathia, incomplete ossification, and increased thoracolumbar vertebrae
  • Clinical Consideration: Advise women of the potential risk to the fetus.
  • Data: No adequate and well-controlled studies have been performed in pregnant women. Rifaximin (Xifaxan; Salix Pharmaceuticals, Inc., Morrisville, NC) was teratogenic in rats at doses of 150-300 mg/kg (approximately 2.5-5 times the clinical dose adjusted for body surface area) and in rabbits at doses of 62.5-1000 mg/kg (approximately 2-33 times the clinical dose adjusted for body surface area).
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Discussion of Specific Agents: Endocrine medications

Birth control pills (oral contraceptives) and hormone replacement

  • Old categorization: Pregnancy category – X

See the list below:

  • Risk summary: Trimesters of risk - First, second, and third. Associated defects and complications - Variable; inflammatory complications common. There is little or no increased risk of birth defects in women who inadvertently use combined oral contraceptives during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy.

See the list below:

  • Clinical consideration: Stop taking the oral contraceptives or hormone replacement as soon as a positive pregnancy test is noted.
  • Data: Little direct data are available because of the lack of models for estrogen-deficient pregnancy.

Corticosteroids (Betamethasone, dexamethasone, fludrocortisone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone)

  • Old categorization: Pregnancy category - C
  • Risk summary: Trimester of risk – First. Associated defects and complications - Reduced birth weight, increased risk of preeclampsia, and increased risk of oral and lip clefts.
  • Clinical considerations: There are no adequate and well-controlled studies in pregnant women. Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism
  • Data: A study of 35 women demonstrated various defects in 9 infants. Concerns have been expressed that neonatal adrenal hyperplasia or insufficiency may result from maternal corticosteroid use. The meaning of these results is uncertain. The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 34 of whom had first-trimester exposure to cortisone. No evidence of a relationship to congenital defects was observed.

Danazol (Danocrine)

  • Old categorization: Pregnancy category - X
  • Risk summary: Trimesters of risk - First, second, and third.  Associated defects and complications: Danazol can cause virilization of the external genital organs, and it has been linked to pseudohermaphroditism.
  • Clinical consideration: Recommend against use in pregnancy due to the risk of virilization.
  • Data: Clinical findings suggest the development of salt-losing congenital adrenal hyperplasia. In one child, basal levels of the adrenal steroids were normal after 1 year. It may be hypothesized that danazol transiently blocked the steroid 21- and 11-beta-monooxygenases in this child. Reversible oligospermia may occur in adult males after prolonged administration or excessive dosage. If this effect occurs, danazol can be discontinued and if restarted, a lower dosage should be utilized.

Estradiol gel 0.06 % (Estrogel, Elestrin)

  • Old categorization: Pregnancy category - C
  • Risk summary: Trimesters of risk - First, second, and third.  Associated defects and complications - Decrease in the quantity and quality of milk
  • Clinical considerations: There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy.
  • Data: No adequate and well-controlled studies of estradiol gel 0.06% (EstroGel; ASCEND Therapeutics, Inc, Herndon, VA) have been performed in pregnant women.

Exenatide (Byetta, Bydureon)

  • Old categorization: Pregnancy category – C
  • Pregnancy risk exposure: 1-800-633-9081
  • Risk summary: Trimester of risk – Unknown. Associated defects and complications - Possible skeletal effects
  • Clinical considerations: There are no adequate and well-controlled studies of exenatide use in pregnant women. In animal studies, exenatide caused cleft palate, irregular skeletal ossification and an increased number of neonatal deaths. Exenatide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
  • Data:  Female mice given SC doses of 6, 68, or 760 mcg/kg/day beginning 2 weeks prior to and throughout mating until gestation day 7 had no adverse fetal effects. At the maximal dose, 760 mcg/kg/day, systemic exposures were up to 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. In developmental toxicity studies, pregnant animals received exenatide subcutaneously during organogenesis. Specifically, fetuses from pregnant rabbits given SC doses of 0.2, 2, 22, 156, or 260 mcg/kg/day from gestation day 6 through 18 experienced irregular skeletal ossifications from exposures 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. Moreover, fetuses from pregnant mice given SC doses of 6, 68, 460, or 760 mcg/kg/day from gestation day 6 through 15 demonstrated reduced fetal and neonatal growth, cleft palate and skeletal effects at systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

Methimazole

  • Old categorization: Pregnancy category – D
  • Risk summary: Trimesters of risk - First, possibly second, and third.  Associated defects and complications - Prematurity, small-for-gestational-age infants, and scalp defects (aplasia cutitis); possible choanal and esophageal atresia, absent or hypoplastic nipples
  • Clinical considerations:  If a patient is using this drug, it may be better to switch to another drug to control her hyperthyroidism in the first trimester, until organogenesis is completed, as this crossed the placenta.  In pregnant women with untreated or inadequately treated Graves’ disease, there is an increased risk of adverse events of maternal heart failure, spontaneous abortion, preterm birth, stillbirth and fetal or neonatal hyperthyroidism.
  • Data: One study indicated that the prevalence of choanal and esophageal atresia may be higher than expected in fetuses exposed to methimazole during gestational weeks 3-7. Some researchers gave stated that no deleterious effects on thyroid function or on the physical and intellectual development occurred when mothers were treated with dosages up to 20 mg/d during pregnancy. Propylthiouracil can be used instead.

Mifepristone, RU-486 (RU-486, Mifeprex, Korlym)

  • Old Categorization: Pregnancy category - D
  • Risk Summary: Trimester of risk – Unknown.  Associated defects and complications - Unknown; possible sexual function
  • Clinical Consideration: Mifepristone is indicated for the termination of pregnancy through 49 days and has no other approved indication for use during pregnancy.
  • Data: Whether mifepristone has teratogenic effects is not known for certain. Children whose mothers used it have been born without birth defects. However, experiments in rats have shown different results. Rats that were exposed to the drug were born normal in one study. However, in another study, sexual function was affected. Therefore, this medication appears to impart some increase in an undefined risk if it is ingested during pregnancy.

Potassium iodide

  • Old Categorization: Pregnancy category - D
  • Risk Summary: Trimester of risk – Unknown.  Associated defects and complications - Hypoplasia, goiter
  • Clinical Consideration: Transplacental passage can cause severe and possibly irreversible hypothyroidism in neonates.  Women and men of childbearing potential should use two forms of effective contraception to avoid pregnancy for at least 6 months after administration of I-131.  Lactating women should not breastfeed.
  • Data: Studies have shown that medications containing potassium iodide (as a radiocontrast agent) can affect the fetal thyroid gland and lead to hypoplasia and goiter.

Progesterones (medroxyprogesterone/Provera, norethindrone/Micronor/aygestin, prometrium)

  • Old Categorization: Pregnancy category
    • Medroxyprogesterone acetate- X
    • Norethindrone- X
    • Prometrium- B
  • Risk Summary: Trimesters of risk - First, second, and third.  Associated defects and complications - Possible cardiovascular defects, hypospadias
  • Clinical Consideration: Progesterones should not be used during pregnancy
  • Data: Various forms of progesterone are used as contraceptive agents and are classified as pregnancy category D or X. They have been linked to birth defects (eg, cardiovascular defects, hypospadias), but this has not been proven.
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Discussion of Specific Agents: Other

Finasteride (Propecia, Proscar)

  • Old categorizartion: Pregnancy category – X
  • Risk summary: Trimesters of risk - First, second, and third. Associated defects and complications - Abnormalities of the sex organs
  • Data: Studies in animals demonstrated that pregnancies sired by male rats given large doses of finasteride did not result in offspring born with birth defects. As of this writing, no such studies have been conducted in humans. Animal studies have shown that pregnant monkeys given large doses of oral finasteride had male offspring with abnormalities of the sex organs. Although highly unlikely, a theoretical risk exists for birth defects of a male fetus' sex organs if a man taking finasteride has intercourse during the stage of pregnancy when the sex organs are developing (8-15 wks of gestation). However, the amount of the drug found in the semen is small and not considered to be enough to harm a male baby.

Folic acid antagonists (aminopterin, carbamazepine, cimetidine, methotrexate, pemetrexed, phenytoin, phenobarbital, proguanil, pyrimethamine, sulfasalazine, triamterene, trimethoprim, valproic acid)

  • Old categorization: Pregnancy category – some are D, some are X
  • Risk summary: Trimester of risk - First, during normal closure of the fetal neural tube. Associated defects and complications - Variable; neural tube defects
  • Data: Dietary factors, such as cholesterol and folic acid, appear to be critical for normal closure of the fetal neural tube. Approximately 50% of neural tube defects can be prevented. To prevent them, a pregnant woman should take supplemental folic acid. The US Public Health Service recommends that all women of childbearing age take 0.4 mg of folic acid per day. The following drugs interfere with folic acid metabolism:
    • Phenobarbital, phenytoin (Dilantin; Parke-Davis, Division of Pfizer Inc), carbamazepine (Tegretol; Novartis Pharmaceuticals Corporation, East Hanover, NJ), and primidone (Mysoline; Valeant Pharmaceuticals International, Aliso Viejo, CA) - Primarily used to prevent seizures. Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two- to three-fold that in the general population. However, the relative contributions of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs.
    • Antibiotic combination of trimethoprim and a sulfonamide (eg, Bactrim; AR Scientific, Philadelphia, PA, and Septra; Monarch Pharmaceuticals, Inc, Bristol, TN) - Commonly used to treat urinary tract infections. While there are no large prospective, well controlled studies in pregnant women and their babies, some retrospective epidemiologic studies suggest an association between first trimester exposure to sulfamethoxazole/trimethoprim with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular abnormalities, urinary tract defects, oral clefts, and club foot.
    • Triamterene (Dyrenium; WellSpring Pharmaceutical Corporation, Bradenton, FL) - Diuretic used to treat high blood pressure
    • Sulfasalazine (Azulfidine; Pharmacia & Upjohn Company, Division of Pfizer Inc) - Used to manage ulcerative colitis and other inflammatory conditions
    • Valproic acid (Depakote; Abbott Laboratories, North Chicago, IL)
    • Cimetidine (Tagamet; GlaxoSmithKline, Research Triangle Park, NC) - Used to treat ulcers and acid reflux
    • Beta-blockers and calcium channel blockers - Used to manage high blood pressure and certain heart disorders
    • Cholestyramine (LoCholest; Warner Chilcott Laboratories, Rockaway, NJ, and Questran; Bristol-Myers Squibb, New York, NY) - Used to lower cholesterol levels
  • The prevalence of birth defects after use of the drugs listed above is highly variable. Defects can often be prevented with folic acid supplementation. Anticonvulsant medications on this list can cause a host of birth defects independent of their effects on folic acid.

Methylene blue

  • Old Categorization: Pregnancy category - C
  • Risk Summary: Trimester of risk – Unknown.  Associated defects and complications - Intestinal atresias
  • Clinical Consideration: Safety for use in pregnancy has not been established.  Use in women of childbearing potential requires benefits be weighed against hazards.
  • Data: Methylene blue is reported to cause intestinal atresias when it is injected into the amniotic fluid during amniocentesis. It poses a small risk of causing birth defects.

Retinoids (Absorica, Accutane, Isotretinoin)

  • Old Categorization: Pregnancy category – X
  • Pregnancy risk exposure: Any suspected fetal exposure during or 1 month after therapy must be reported immediately to the FDA via MedWatch (1-800-FDA-1088) and also iPLEDGE pregnancy registry (1-866-495-0654 or www.ipledgeprogram.com
  • Risk Summary: Trimesters of risk: The first, second, and third trimesters are times of risk. The critical window of exposure is at 3-5 weeks of pregnancy.
    • Associated defects and complications - Deformities of the cranium, ears, face, limbs, and liver; hydrocephalus; microcephalus; heart defects; cognitive defects without dysmorphology; craniofacial alterations; cleft palate; neural tube defects; cardiovascular malformations; thymic aplasia; psychological impairments; absent or defective ears; small jaw; and kidney alterations
  • Clinical Consideration: Female patients of childbearing potential must use two forms of effective contraception simultaneously.  If pregnancy occurs, the drug must be stopped.).
  • Data: Retinoic acid is teratogenic in humans at low doses. Of affected children, 50% have an intelligence quotient (IQ) of less than 85. The mean IQ score is 100-110. Retinoic acid is the active ingredient in Accutane (Roche Laboratories Inc, Nutley, NJ), a drug used to treat severe acne. Since its introduction in September 1982, an estimated 160,000 women of childbearing age have used it. From 1982-1987, approximately 900-1300 malformed children, 700-1000 spontaneous abortions, and 5000-7000 elective abortions were attributed to exposure to this drug. Exposed children may have had hydrocephaly, ear malformations, cardiovascular defects, and decreased IQ scores. Accutane carries a pregnancy category X warning; it is a known human teratogen. Dosages of 25,000 IU/d or more, given in the form of retinol or retinyl esters, should be considered potentially teratogenic. Another strategy involves the administration of drugs during pregnancy while accounting for its pharmacologic effects in relation to the gestational period. Examples are avoidance of chemotherapy during the first trimester, avoidance of nonsteroidal anti-inflammatory drugs in the third trimester, avoidance of high doses of benzodiazepines in the period when events are imminent. Only a minimal amount of tazarotene is absorbed into the circulation.

Warfarin (Coumadin)

  • Old Categorization: Pregnancy category - X
  • Risk Summary: Trimesters of risk - First, second, and third. Associated defects and complications - Deformities of the axial and appendicular skeleton; also, a hypoplastic nose, eye abnormalities, mental retardation, brachydactyly, and scoliosis
  • Clinical Consideration: Warfarin is contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism. Monitor breastfeeding infants for bruising or bleeding. Verify the pregnancy status of females of reproductive potential prior to initiating warfarin therapy. Advise females of reproductive potential to use effective contraception during treatment, and for at least 1 month after the final dose.
  • Data: Malformations are reported in 16% of exposed fetuses; hemorrhages, in 3%; and stillbirths, in 8%. The embryopathy described above results from maternal use during early pregnancy, whereas CNS disorders are due to ingestion at a later stage in pregnancy. The teratogenic mechanism of warfarin is unknown, but one proposed theory is that an alteration in posttranslational carboxylation of proteins may result in the chondrogenic disorders
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Contributor Information and Disclosures
Author

Brittney D Bastow, MD Instructor, Department of Obstetrics and Gynecology, University of Colorado School of Medicine

Brittney D Bastow, MD is a member of the following medical societies: Alpha Omega Alpha, American Congress of Obstetricians and Gynecologists, Society for Academic Specialists in General Obstetrics and Gynecology

Disclosure: Nothing to disclose.

Coauthor(s)

Jennifer L Holmes, MD, MS Assistant Professor, Department of Obstetrics and Gynecology, University of Colorado School of Medicine; Physician, University of Colorado Women’s Care Clinic

Jennifer L Holmes, MD, MS is a member of the following medical societies: American College of Obstetricians and Gynecologists

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Christine Isaacs, MD Associate Professor, Department of Obstetrics and Gynecology, Division Head, General Obstetrics and Gynecology, Medical Director of Midwifery Services, Virginia Commonwealth University School of Medicine

Christine Isaacs, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists

Disclosure: Nothing to disclose.

Additional Contributors

Suzanne R Trupin, MD, FACOG Clinical Professor, Department of Obstetrics and Gynecology, University of Illinois College of Medicine at Urbana-Champaign; CEO and Owner, Women's Health Practice; CEO and Owner, Hada Cosmetic Medicine and Midwest Surgical Center

Suzanne R Trupin, MD, FACOG is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, International Society for Clinical Densitometry, AAGL, North American Menopause Society, American Medical Association, Association of Reproductive Health Professionals

Disclosure: Nothing to disclose.

Joy C Draper, JD, MD, FACOG Assistant Professor, Department of Obstetrics and Gynecology, Medical College of Virginia Hospitals, Virginia Commonwealth University School of Medicine

Joy C Draper, JD, MD, FACOG is a member of the following medical societies: American Academy of Family Physicians, American College of Obstetricians and Gynecologists

Disclosure: Nothing to disclose.

Kirk J Matthews, Jr, MD Resident Physician, Department of Obstetrics and Gynecology, Virginia Commonwealth University Medical Center

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors Noah S Scheinfeld, MD, JD, FAAD, Anne Davis, MD, MPH, FACOG, Jessica M Allan, MD, and Rachel Nazarian to the development and writing of this article.

References
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